Reactive oxygen species have a causal role in multiple forms of insulin resistance

Abstract

Insulin resistance is a cardinal feature of type 2 diabetes and is characteristic of a wide range of other clinical and experimental settings. Little is known about why insulin resistance occurs in so many contexts. Do the various insults that trigger insulin resistance act through a common mechanism? Or, as has been suggested, do they use distinct cellular pathways? Here we report a genomic analysis of two cellular models of insulin resistance, one induced by treatment with the cytokine tumour-necrosis factor-alpha and the other with the glucocorticoid dexamethasone. Gene expression analysis suggests that reactive oxygen species (ROS) levels are increased in both models, and we confirmed this through measures of cellular redox state. ROS have previously been proposed to be involved in insulin resistance, although evidence for a causal role has been scant. We tested this hypothesis in cell culture using six treatments designed to alter ROS levels, including two small molecules and four transgenes; all ameliorated insulin resistance to varying degrees. One of these treatments was tested in obese, insulin-resistant mice and was shown to improve insulin sensitivity and glucose homeostasis. Together, our findings suggest that increased ROS levels are an important trigger for insulin resistance in numerous settings.

Glucagon‐like peptide‐1 ameliorates cardiac lipotoxicity in diabetic cardiomyopathy via the PPARα pathway

“…Diabetes‐induced CM apoptosis has been associated with excessive generation of reactive free radicals even though other inductive pathways exist as well (Dorn, 2009; Robertson et al., 2004). Increased ROS production and reduced antioxidant levels in diabetes have been widely documented in previous reports (Fiordaliso et al., 2004; Houstis et al., 2006). Earlier studies showed that CMs incubated with GLP‐1 or its analogs remained viable and lowered ROS levels and apoptosis rates in both diabetic and nondiabetic models (Inoue et al., 2015; Raab, Vuguin, Stoffers & Simmons, 2009; XiaoTian et al., 2016).…”

“…Although the switching of substrate utilization may meet the energy demand for heart function maintenance, it also brings many deleterious consequences (Rodrigues, Cam & McNeill, 1995; Stanley, Lopaschuk & McCormack, 1997). Increased fatty acid (FA) oxidation along with reduced ATP/O ratios decreases cardiac efficiency and contributes to ventricular dysfunction by increasing the generation of reactive oxygen species (ROS) and toxic lipid intermediates (Battiprolu et al., 2013; Houstis, Rosen & Lander, 2006). ROS damage DNA, mitochondria, and other cellular components by oxidizing proteins, converting lipids into reactive lipid peroxides, and increasing protein tyrosine nitration (Boudina et al., 2005).…”

Neuroendocrine mechanisms in insulin resistance

“…It was previously reported that dexamethasone-induced insulin resistance in adipose cells is A c c e p t e d M a n u s c r i p t 16 associated with ROS formation (90). Interestingly, insulin resistance was prevented by overexpression of ROS-metabolizing enzymes.…”

“…Inflammatory cytokines can increase oxidative stress, and there are results suggesting that this can be mediated via ceramide formation that stimulates mitochondrial ROS production. In adipose cells, TNF- can thus increase ROS levels that will activate the stress kinase JNK that in turn may increase IRS-1 serine phosphorylation (8,90). Thus, metabolic as well as inflammatory cellular stress can converge into a final pathway of oxidative stress.…”

Increased susceptibility to oxidative damage in post-diabetic human myotubes

“…ROS can cause lipid peroxidation, generating products such as methylcholanthrene and 4-hydroxynonenal (HNE), which can subsequently bind proteins, forming adducts and impairing protein function, as reviewed by Eriksson [21], Pieczenik and Neustadt [22], and Civitarese and Ravussin [23]. Oxidative stress has been implicated in the development of insulin resistance [24][25][26][27][28]; however the role of ROS in diabetic skeletal muscle is an emerging field. Recently, Chung et al demonstrated that treatment of human skeletal muscle cells with high levels of hydrogen peroxide led to destruction of the insulin signalling pathway, but that pretreatment with troglitazone could prevent this ROS-induced insulin resistance [29].…”